title: Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition.
abstract: Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys).
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. barbara.burtness@fccc.edu
authors.forename: Barbara
authors.initials: B
authors.lastname: Burtness
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.forename: Thomas
authors.initials: T
authors.lastname: Galloway
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000821:virology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D027383:Papillomaviridae / Q000302:isolation & purification*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human